Abstract | PURPOSE: METHODS: CEM/0, seven ara-C- and/or ASNase-resistant clones, Jurkat/0, the myelomonocytic line U937 and U87 MG glioblastoma cell lines were used for these studies. The drug-resistant leukemic clones lack p53, express bcl-2 and VEGF-R1, and thus are refractory to apoptosis. Since tyrosine kinases drive many proliferative pathways and these activities are increased in many leukemic cells, we hypothesized that NSC 680410 may induce cytotoxicity in drug-resistant leukemia clones, independently of p210bcr/abl expression. RESULTS:
NSC 680410 exhibited significant antileukemic activity in CEM/0, Jurkat E6-1, and in the drug-resistant leukemic cell lines. The IC(50) values in nine leukemia lines ranged from 17 to 216 n M. Western blot analyses after NSC 680410 treatment demonstrated caspase-3 cleavage and ELISAs showed a fivefold upregulation of its activity in cellular extracts. In addition, U87 MG human glioblastoma cells, which express VEGF-R1, were treated with the Flt-1/Fc chimera, a specific inhibitor of VEGF, and showed 30-43% cell kill in the MTT assay. Furthermore, the combination of NSC 680410 plus Flt-1/Fc chimera demonstrated an eightfold synergism against U87 MG cells in vitro. To verify this observation in vivo, athymic mice were inoculated orthotopically into the caudate putamen with 10(6) U87 MG cells. On day 3, five mice per group were treated i.p. with either 8.3 mg/kg NSC 680410 daily for three doses per week for 4 weeks alone or in combination with one dose of Flt-1/Fc chimera 100 mg/kg subcutaneously. Treatment with NSC 680410 alone produced no weight changes and increased the median survival to 133%, whereas treatment with NSC680410 plus Flt-1/Fc chimera increased survival to 142% over control. Control animals had large intra- and extracranial tumors while the NSC 680410-treated mice had small, only intracranial tumors with necrotic centers. The combination treatment resulted in small residual tumors around the needle track, indicating significant inhibition of tumor growth. CONCLUSIONS:
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Authors | Ioannis A Avramis, Garyfallia Christodoulopoulos, Atsushi Suzuki, Walter E Laug, Ignacio Gonzalez-Gomez, George McNamara, Edward A Sausville, Vassilios I Avramis |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 50
Issue 6
Pg. 479-89
(Dec 2002)
ISSN: 0344-5704 [Print] Germany |
PMID | 12451475
(Publication Type: Journal Article)
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Chemical References |
- DNA, Neoplasm
- Endothelial Growth Factors
- Enzyme Inhibitors
- Extracellular Matrix Proteins
- Hydroquinones
- Intercellular Signaling Peptides and Proteins
- Lymphokines
- NSC 680410
- Proto-Oncogene Proteins c-bcl-2
- Vascular Endothelial Growth Factor A
- Vascular Endothelial Growth Factors
- FLT1 protein, human
- Flt1 protein, mouse
- Protein-Tyrosine Kinases
- Vascular Endothelial Growth Factor Receptor-1
- Fusion Proteins, bcr-abl
- CASP3 protein, human
- Casp3 protein, mouse
- Caspase 3
- Caspases
- Nonmuscle Myosin Type IIB
- nonmuscle myosin type IIB heavy chain
- Myosin Heavy Chains
- Adamantane
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Topics |
- Adamantane
(analogs & derivatives, therapeutic use)
- Animals
- Blotting, Western
- Brain Neoplasms
(drug therapy, genetics, metabolism)
- Caspase 3
- Caspases
(metabolism)
- DNA, Neoplasm
(metabolism)
- Drug Resistance, Neoplasm
- Endothelial Growth Factors
(metabolism)
- Enzyme Inhibitors
(therapeutic use)
- Enzyme-Linked Immunosorbent Assay
- Extracellular Matrix Proteins
(pharmacology)
- Female
- Fusion Proteins, bcr-abl
(antagonists & inhibitors, metabolism)
- Glioblastoma
(drug therapy, genetics, metabolism)
- Humans
- Hydroquinones
(therapeutic use)
- In Vitro Techniques
- Intercellular Signaling Peptides and Proteins
(metabolism)
- Leukemia, T-Cell
(drug therapy, genetics, metabolism)
- Lymphokines
(metabolism)
- Mice
- Mice, Nude
- Myosin Heavy Chains
- Neoplasm Transplantation
- Nonmuscle Myosin Type IIB
- Protein-Tyrosine Kinases
(antagonists & inhibitors)
- Proto-Oncogene Proteins c-bcl-2
(metabolism)
- Tumor Cells, Cultured
(drug effects, metabolism)
- Vascular Endothelial Growth Factor A
- Vascular Endothelial Growth Factor Receptor-1
(metabolism)
- Vascular Endothelial Growth Factors
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